Nuyens, who was hired by Saxo Bank after classics giant Fabian Cancellara left the team, dominated a three-man sprint to beat Quick Step's Sylvain Chavanel, with Cancellara, the defending champion, in third after 256km of racing.
Cancellara lined up as virtually the only favourite for the second cycling 'monument' of the season having coasted to victory in a smaller classic race in midweek, and by virtue of his unrivalled domination of Flanders and Paris-Roubaix last year.
However, in the end the big Leopard-Trek rider was undone by his comparative lack of sprinting prowess. Nuyens, second in Flanders in 2008, spent years working as a support sprinter for former two-time winner Tom Boonen at Quick Step.
After a thrilling final 30km in which Cancellara and Chavanel were caught by a small select bunch of contenders, the big Swiss found himself with Nuyens and the Frenchman for company in the final few kilometres, and with Boonen bearing down.
Cancellara hit full gas with 200 metres to go, however Nuyens sprung from out behind the Swiss's wheel in the final 50 to come over the finish line in triumph.
Chavanel, a two-time stage winner at last year's Tour de France, was making his race debut and only narrowly missed victory after being blocked into the barriers as he launched a late bid for success.
Nuyens' previous victories include Kuurne-Brussels-Kuurne (2006), Omloop Het Volk (2005), and Paris-Brussels (2004). He has also won the GP de Wallonie three times (2004, 2005 and 2008).
Despite this setback, Cancellara is likely to saddle up as the favourite again when Paris-Roubaix, ominously named the 'Hell of the North', is held next Sunday.
Cancellara's Australian teammate Stuart O'Grady finished 69th - 12.37 minutes behind the winner.
